The success of surgical transplantation of organs and tissue is largely dependent on the ability of the clinician to modulate the immune response of the transplant recipient. Specifically, the immunological response directed against the transplanted foreign tissue must be controlled if the tissue is to survive and function. It is known that the normally functioning immune system of the transplant recipient recognizes the transplanted organ as “non-self” tissue and thereafter mounts an immune response to the presence of the transplanted organ. Left unchecked, the immune response will generate a multitude of cells and proteins that will ultimately result in the loss of biological functioning or the death of the transplanted organ.
Transplant rejection remains the leading impediment to long term graft survival in humans. Currently, tissue and organ transplant recipients are typically treated with one or more cytotoxic agents in an effort to suppress the transplant recipient's immune response against the transplanted organ or tissue. For example, cyclosporin A, a cyclic peptide consisting of 11 amino acid residues and produced by the fungus species Tolypocladium Inflatum Gams is currently used to administer to the recipients of kidney, liver, pancreas and heart allografts (i.e., wherein donor and recipient are of the same species). However, administration of cyclosporin A is not without drawbacks as the drug can cause kidney and liver toxicity as well as hypertension. Moreover, the use of cyclosporin A can lead to malignancies (such as lymphoma) and lead to opportunistic infection due to the systemic immunosuppression it induces in patients receiving long term treatment with the drug, i.e., the normal protective immune response of the host to pathogenic microorganisms is downregulated thereby increasing the risk of infections caused by such microorganisms.
Currently available immunosuppressive agents such as cyclosporin A fail to prevent either acute or chronic refractory rejection. It is estimated that nearly 20% of cadaver kidney and cardiac grafts are lost during the first year post-transplant, primarily due to acute rejection. Chronic rejection poses formidable hurdles for extant immunosuppressant therapies. Studies have shown that 50% of lung transplant recipients develop bronchitis obliterans, the hallmark of chronic allograft rejection. Some studies have shown that only 20% of cadaver renal transplants continue to function at ten years post-transplant. Transplant vasculopathy, induced by chronic rejection and ischemia, is the leading cause of cardiac transplant graft loss after the first year post transplant. Moreover, current post-transplantation therapy requires continuous (e.g., daily) administration of an anti-rejection agent for the duration of the transplant recipient's life.
Therefore, there is a continuing need for new methods for improving the transplantation outcome in a mammalian cell, tissue, or organ transplant recipient.